U.S. patent number 9,061,065 [Application Number 14/031,657] was granted by the patent office on 2015-06-23 for intracameral sustained release therapeutic agent implants.
This patent grant is currently assigned to Allergan, Inc.. The grantee listed for this patent is Allergan, Inc.. Invention is credited to James A. Burke, Alazar N. Ghebremeskel, Michael R. Robinson, Rhett M. Schiffman.
United States Patent |
9,061,065 |
Robinson , et al. |
June 23, 2015 |
Intracameral sustained release therapeutic agent implants
Abstract
Described herein are intracameral implants including at least
one therapeutic agent for treatment of at least one ocular
condition. The implants described herein are not anchored to the
ocular tissue, but rather are held in place by currents and gravity
present in the anterior chamber of an eye. The implants are
preferably polymeric, biodegradable and provide sustained release
of at least one therapeutic agent to both the trabecular meshwork
and associated ocular tissue and the fluids within the anterior
chamber of an eye.
Inventors: |
Robinson; Michael R. (Irvine,
CA), Burke; James A. (Santa Ana, CA), Schiffman; Rhett
M. (Laguna Beach, CA), Ghebremeskel; Alazar N. (Irvine,
CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
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Assignee: |
Allergan, Inc. (Irvine,
CA)
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Family
ID: |
43795202 |
Appl.
No.: |
14/031,657 |
Filed: |
September 19, 2013 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20140045945 A1 |
Feb 13, 2014 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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13011467 |
Jan 21, 2011 |
8647659 |
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61297660 |
Jan 22, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/0024 (20130101); A61P 27/06 (20180101); A61K
31/5575 (20130101); A61L 27/18 (20130101); A61K
47/34 (20130101); A61P 27/02 (20180101); A61K
9/0051 (20130101); A61L 27/58 (20130101); A61K
47/10 (20130101); A61L 27/54 (20130101); A61K
9/1647 (20130101) |
Current International
Class: |
A61K
47/34 (20060101); A61K 9/00 (20060101); A61K
47/10 (20060101); A61K 9/16 (20060101); A61L
27/18 (20060101); A61L 27/54 (20060101); A61L
27/58 (20060101); A61K 31/5575 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2010-056598 |
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May 2010 |
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WO |
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2011-109384 |
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Sep 2011 |
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WO |
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2011-109384 |
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Sep 2011 |
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WO |
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2012-149278 |
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Nov 2012 |
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WO |
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2012-149287 |
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Nov 2012 |
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WO |
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Primary Examiner: Azpuru; Carlos
Attorney, Agent or Firm: Wine; Laura L. German; Joel B.
Condino; Debra D.
Parent Case Text
CROSS-REFERENCE
This application is a divisional of U.S. application Ser. No.
13/011,467, filed on Jan. 21, 2011, which claims the benefit of
U.S. Provisional Patent Application Ser. No. 61/297,660, filed on
Jan. 22, 2010, the entire disclosure of which is incorporated
herein by this specific reference. The entire disclosure of U.S.
application Ser. No. 13/011,467 is incorporated herein by
reference.
Claims
We claim:
1. A method for treating glaucoma in an eye comprising the steps
of: providing at least two biodegradable sustained release implants
containing at least one therapeutic agent; implanting the at least
two biodegradable sustained release implants into the anterior
chamber of the eye; and treating the glaucoma, wherein each of the
at least two biodegradable sustained release implants releases
about 100 ng per day to about 900 ng per day of the at least one
therapeutic agent over the lifetime of the implant, and wherein the
at least two biodegradable sustained release implants each comprise
about 5% to about 40% of the least one therapeutic agent, about 10%
to about 60% R203S, which is a poly(D,L-lactide) having an inherent
viscosity of about 0.25 to about 0.35 dl/g, about 5% to about 20%
R202H, which is a poly(D,L-lactide) having an inherent viscosity of
about 0.16 to about 0.24 dl/g, about 5% to about 40% RG752S, which
is a poly(D,L-lactide-co-glycolide) having a D,L-lactide:glycolide
molar ratio of about 73:27 to about 77:23 and an inherent viscosity
of about 0.16 to about 0.24 dl/g, and about 5% to about 15%
polyethylene glycol (PEG).
2. The method according to claim 1, wherein the at least one
therapeutic agent is selected from the group consisting of
latanoprost, bimatoprost and travoprost.
3. The method according to claim 1, wherein the at least one
therapeutic agent is a prostamide.
4. The method according to claim 1, wherein the at least one
therapeutic agent is bimatoprost.
5. The method according to claim 1, wherein the at least two
biodegradable sustained release implants each comprise about 20%
bimatoprost, about 45% R203S, about 10% R202H, about 20% RG752S,
and about 5% polyethylene glycol (PEG).
6. The method according to claim 1, wherein each of the at least
two biodegradable sustained release implants is produced by an
extrusion method.
Description
FIELD OF THE INVENTION
The present invention relates to intracameral sustained release
implants and methods of making and using the same.
SUMMARY
Described herein are intraocular systems and methods for treating
ocular conditions. In particular, local administration of a
sustained release therapeutic agent delivery system to the anterior
chamber and/or to anterior vitreous chamber of the eye to treat
aqueous chamber elevated intraocular pressure is described.
Further, described herein are methods for treating an ocular
condition comprising the steps of: providing at least two
biodegradable sustained release implants containing at least one
therapeutic agent; implanting the at least two biodegradable
sustained release implants into the anterior chamber of an eye; and
treating the ocular condition, wherein the at least two
biodegradable sustained release implants release about 100 ng per
day of the at least one bioactive agent for a period greater than
about 1 month.
Further still, described herein are methods for treating glaucoma
in an eye comprising the steps of: providing at least two
biodegradable sustained release implants containing at least one
therapeutic agent; implanting the at least two biodegradable
sustained release implants into the anterior chamber of the eye;
allowing a sufficient time for the at least two biodegradable
sustained release implants to settled out in the inferior angle;
allowing a sufficient time for the at least two biodegradable
sustained release implants to release the at least one therapeutic
agent; and treating glaucoma, wherein the at least two
biodegradable sustained release implants release about 100 ng per
day of the at least one bioactive agent for a period greater than
about 1 month.
In one embodiment, the ocular condition is glaucoma and/or elevated
intraocular pressure. The sustained release implants can release
about 70% of the at least one therapeutic agent over the first
month. In some embodiments, the at least one therapeutic agent can
comprise about 30% of the at least two biodegradable sustained
release implants and is selected from the group consisting of
latanoprost, bimatoprost and travoprost and their salts, esters and
prodrugs.
In another embodiment, the at least two biodegradable sustained
release implants comprise about 5% to about 70% poly(D,L-lactide).
In other embodiments, the at least two biodegradable sustained
release implants comprise about 5% to about 40%
poly(DL-lactide-co-glycolide). In yet other embodiments, the at
least two biodegradable sustained release implants comprise about
5% to about 40% polyethylene glycol.
In still other example embodiments, the at least two biodegradable
sustained release implants comprise about 30% therapeutic agent,
65% poly(D,L-lactide), and 5% polyethylene glycol or about 20%
therapeutic agent, 55% poly(D,L-lactide), 10%
poly(DL-lactide-co-glycolide), and 5% polyethylene glycol.
The implants themselves can be inserted into the ocular tissue
using an appropriate applicator. Once implanted, the at least two
biodegradable sustained release implants can settle out in the
inferior angle within 24 hours of implanting within the anterior
chamber.
In one embodiment, the the sufficient time for the at least two
biodegradable sustained release implants to release the at least
one therapeutic agent is greater than about 42 days.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates the two different pathways for aqueous humor
outflow from the anterior chamber both located in the iridocorneal
angle.
FIG. 2 illustrates the placement of an implant as described herein
at the location of aqueous humor outflow from the anterior
chamber.
FIG. 3 illustrates the currents located within the anterior chamber
of an eye as well as a possible location of an implant or implants
as described herein.
FIG. 4 graphically illustrates a release profile of implants of the
present description.
FIG. 5 graphically illustrates a release profile of implants of the
present description.
FIG. 6 illustrates the placement of an implant according the
present description.
DEFINITION OF TERMS
"About" means plus or minus ten percent of the number, parameter or
characteristic so qualified.
"Biodegradable polymer" means a polymer or polymers which degrade
in vivo, and wherein erosion of the polymer or polymers over time
occurs concurrent with or subsequent to release of the therapeutic
agent. The terms "biodegradable" and "bioerodible" are used
interchangeably herein. A biodegradable polymer may be a
homopolymer, a copolymer, or a polymer comprising more than two
different polymeric units. The polymer can be a gel or hydrogel
type polymer, polylactic acid or poly(lactic-co-glycolic) acid or
polyethylene glycol polymer or mixtures or derivatives thereof.
"Ocular condition" means a disease, ailment or condition which
affects or involves the ocular region. Broadly speaking, the eye
includes the eyeball and the tissues and fluids which constitute
the eyeball, the periocular muscles (such as the oblique and rectus
muscles) and the portion of the optic nerve which is within or
adjacent to the eyeball.
An anterior ocular condition is a disease, ailment or condition
which affects or which involves an anterior (i.e. front of the eye)
ocular region or site, such as a periocular muscle, an eye lid or
an eye ball tissue or fluid which is located anterior to the
posterior wall of the lens capsule or ciliary muscles. Thus, an
anterior ocular condition primarily affects or involves the
conjunctiva, the cornea, the anterior chamber, the iris, the
posterior chamber (behind the retina but in front of the posterior
wall of the lens capsule), the lens or the lens capsule and blood
vessels and nerve which vascularize or innervate an anterior ocular
region or site.
Thus, an anterior ocular condition can include a disease, ailment
or condition, such as for example, aphakia; pseudophakia;
astigmatism; blepharospasm; cataract; conjunctival diseases;
conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes;
eyelid diseases; lacrimal apparatus diseases; lacrimal duct
obstruction; myopia; presbyopia; pupil disorders; refractive
disorders and strabismus. Glaucoma can also be considered to be an
anterior ocular condition because a clinical goal of glaucoma
treatment can be to reduce a hypertension of aqueous fluid in the
anterior chamber of the eye (i.e. reduce intraocular pressure).
A posterior ocular condition is a disease, ailment or condition
which primarily affects or involves a posterior ocular region or
site such as choroid or sclera (in a position posterior to a plane
through the posterior wall of the lens capsule), vitreous, vitreous
chamber, retina, optic nerve (i.e. the optic disc), and blood
vessels and nerves which vascularize or innervate a posterior
ocular region or site.
Thus, a posterior ocular condition can include a disease, ailment
or condition, such as for example, acute macular neuroretinopathy;
Behcet's disease; choroidal neovascularization; diabetic uveitis;
histoplasmosis; infections, such as fungal or viral-caused
infections; macular degeneration, such as acute macular
degeneration, non-exudative age related macular degeneration and
exudative age related macular degeneration; edema, such as macular
edema, cystoid macular edema and diabetic macular edema; multifocal
choroiditis; ocular trauma which affects a posterior ocular site or
location; ocular tumors; retinal disorders, such as central retinal
vein occlusion, diabetic retinopathy (including proliferative
diabetic retinopathy), proliferative vitreoretinopathy (PVR),
retinal arterial occlusive disease, retinal detachment, uveitic
retinal disease; sympathetic opthalmia; Vogt Koyanagi-Harada (VKH)
syndrome; uveal diffusion; a posterior ocular condition caused by
or influenced by an ocular laser treatment; posterior ocular
conditions caused by or influenced by a photodynamic therapy,
photocoagulation, radiation retinopathy, epiretinal membrane
disorders, branch retinal vein occlusion, anterior ischemic optic
neuropathy, non-retinopathy diabetic retinal dysfunction, retinitis
pigmentosa, and glaucoma. Glaucoma can be considered a posterior
ocular condition because the therapeutic goal is to prevent the
loss of or reduce the occurrence of loss of vision due to damage to
or loss of retinal cells or optic nerve cells (i.e.
neuroprotection).
"Ocular region" or "ocular site" means any area of the eyeball,
including the anterior and posterior segment of the eye, and which
generally includes, but is not limited to, any functional (e.g.,
for vision) or structural tissues found in the eyeball, or tissues
or cellular layers that partly or completely line the interior or
exterior of the eyeball. Specific examples of areas of the eyeball
in an ocular region include the anterior (aqueous) chamber, the
posterior chamber, the vitreous cavity, the choroid, the
suprachoroidal space, the conjunctiva, the subconjunctival space,
the episcleral space, the intracorneal space, the epicorneal space,
the sclera, the pars plana, surgically-induced avascular regions,
the macula, and the retina.
"Sustained release" or "controlled release" refers to the release
of at least one therapeutic bioactive agent, or drug, from an
implant at a predetermined rate. Sustained release implies that the
therapeutic bioactive agent is not released from the implant
sporadically in an unpredictable fashion and does not "burst" from
the implant upon contact with a biological environment (also
referred to herein as first order kinetics) unless specifically
intended to do so. However, the term "sustained release" as used
herein does not preclude a "burst phenomenon" associated with
deployment. In some example embodiments according to the present
description an initial burst of at least one therapeutic agent may
be desirable followed by a more gradual release thereafter. The
release rate may be steady state (commonly referred to as "timed
release" or zero order kinetics), that is the at least one
therapeutic agent is released in even amounts over a predetermined
time (with or without an initial burst phase) or may be a gradient
release. For example, sustained release can have substantially no
fluctuations in therapeutic agent delivery as compared to topical
administration.
"Therapeutically effective amount" means level or amount of agent
needed to treat an ocular condition, or reduce or prevent ocular
injury or damage without causing significant negative or adverse
side effects to the eye or a region of the eye. In view of the
above, a therapeutically effective amount of a therapeutic agent,
such as a latanoprost, is an amount that is effective in reducing
at least one symptom of an ocular condition.
DETAILED DESCRIPTION
Described herein are intracameral implants including at least one
therapeutic agent. The implants described herein are placed in the
anterior chamber of an eye, but are not anchored to the ocular
tissue. Rather, the implants are held in place by currents and
gravity present in the anterior chamber of the eye. The implants
are preferably polymeric, biodegradable and provide sustained
release of at least one therapeutic agent to both the trabecular
meshwork (TM) and associated ocular tissues, and the fluids within
the anterior chamber of the implanted eye.
Direct intracameral or anterior intravitreal administration of
sustained release implants or therapeutic agent delivery systems,
as set forth herein, are effective in treating an array of ocular
conditions outlined herein. On such condition is glaucoma
characterized by elevated intraocular pressure which can be treated
as described herein by bypassing the robust scleral drug clearance
mechanisms (e.g. topical drops).
Intraocular pressure (IOP) variation appears to be an independent
risk factor for glaucomatous damage. Conventional therapy for
treating ocular hypertension or glaucoma is the use of
anti-hypertensive topical ophthalmic drops to lower the IOP.
Unfortunately, bolus dosing with topical ophthalmic drops results
in anterior chamber therapeutic agent levels with peak and trough
levels that results in variability of IOP control over time. This
fluctuation in IOP can result in glaucomatous field progression,
especially in patients with advanced glaucoma. Addressing this
unmet need in patients with ocular hypertension or glaucoma that
require medical therapy, are the sustained-release intracameral
implants described herein. The implants can establish low
fluctuations of the IOP throughout the day and the night when
topical drops are inconvenient. A nocturnal IOP spike occurs
between 11 pm and 6 am in patients with open angle glaucoma, and
this may contribute to progressive visual field loss in some
patients. The additional limitation of topical therapy is the lack
of steady state drug concentrations in the anterior chamber with
bolus dosing not controlling nocturnal IOP elevations in a number
of patients. The implants described herein establish low
fluctuations of the IOP throughout the night as well, thereby
alleviating the complications of topical administration in the
nighttime hours.
Non-compliance with a medical regimen containing one or more
topical eye drops to treat ocular hypertension or glaucoma occurs
in over 50% of patients and this may contribute to lop fluctuation
during the day when drops are not used on a regular schedule. The
implants described herein do not require such compliance, and are
therefore more patient friendly.
Described herein are intracameral sustained release therapeutic
agent implants that provide continuous release of the therapeutic
agent thereby avoiding the peak and trough therapeutic agent levels
that occur in the aqueous humor with topical dosing. The steady
state drug concentrations achieved in the aqueous humor with the
implants described herein can significantly lower the IOP
fluctuation during the day and night unlike conventional topical
administration of drugs.
The anterior and posterior chambers of the eye are filled with
aqueous humor, a fluid predominantly secreted by the ciliary body
with an ionic composition similar to the blood. The function of the
aqueous humor is two-fold: 1) to supply nutrients to the avascular
structures of the eye, such as the lens and cornea, 2) maintain IOP
within its physiological range. Maintenance of IOP and supply of
nutrients to the anterior segment are factors that are critical for
maintaining normal visual acuity.
Aqueous humor is predominantly secreted to the posterior chamber of
the eye by the ciliary processes of the ciliary body and a minor
mechanism of aqueous humor production is through ultrafiltration
from arterial blood (FIG. 1). Aqueous humor then reaches the
anterior chamber by crossing the pupil and there are convection
currents where the flow of aqueous adjacent to the iris is upwards,
and the flow of aqueous adjacent to the cornea flows downwards
(FIG. 2).
There are two different pathways of aqueous humor outflow, both
located in the iridocorneal angle of the eye (FIG. 1). The
uveoscleral or nonconventional pathway refers to the aqueous humor
leaving the anterior chamber by diffusion through intercellular
spaces among ciliary muscle fibers. Although this seems to be a
minority outflow pathway in humans, the uveoscleral or
nonconventional pathway is the target of specific anti-hypertensive
drugs such as the hypotensive lipids that increase the
functionality of this route through remodeling of the extracellular
matrix.
The aqueous humor drains 360 degrees into the trabecular meshwork
that initially has pore size diameters ranging from 10 to under 30
microns in humans. Aqueous humor drains through Schlemm's canal and
exits the eye through 25 to 30 collector channels into the aqueous
veins, and eventually into the episcleral vasculature and veins of
the orbit (see FIG. 3). FIG. 3 is a schematic drawing in which the
arrows indicate aqueous humor convection currents in the anterior
chamber of an eye. An implant as described herein releasing at
least one therapeutic agent is shown placed inferiorly. Free
therapeutic agents eluting from the implant enters the aqueous
humor convection currents (arrows). The therapeutic agents are then
dispersed throughout the anterior chamber and enter the target
tissues such as the trabecular meshwork and the ciliary body region
through the iris root region.
An advantage of intracameral injection and placement of the
biodegradable implant described herein is that the anterior chamber
is an immune privileged site in the body and less likely to react
to foreign material, such as polymeric therapeutic agent delivery
systems. This is not the case in the sub-Tenon's space where
inflammatory reactions to foreign materials are common. In addition
to the anterior chamber containing immunoregulatory factors that
confer immune privilege, particles with diameters greater than 30
microns are less immunogenic and have a lower propensity toward
causing ocular inflammation. Resident macrophages in the eye are
the first line of defense with foreign bodies or infectious agents;
however, particles larger than 30 microns are difficult to
phagocytose. Therefore, particles larger than 30 microns are less
prone to macrophage activation and the inflammatory cascade that
follows. This reduction in inflammation response is beneficial to a
patient.
The efficiency of delivering therapeutic agents or drugs to the
aqueous humor with a polymeric release system is much greater with
an intracameral location when compared to a sub-Tenon application.
Thus, less than 1% of therapeutic agent delivered in the
sub-Tenon's space will enter the aqueous humor whereas 100% of the
drug released intracamerally will enter the aqueous humor.
Therefore, lower therapeutic agent loads are required for the
intracameral drug delivery systems described herein compared to
sub-Tenon's applications.
As such, there will be less exposure of the conjunctiva to
therapeutic agents, and as a result, less propensity toward
developing conjunctival hyperemia when delivering topical
therapeutic agents, such as prostaglandins and prostamines. Lastly,
the therapeutic agent(s) will enter the conjunctival/episcleral
blood vessel via the aqueous veins directly following intracameral
implantation. This minimizes conjunctival hyperemia with, for
example, prostaglandin analogues compared with a sub-Tenon's
injection where numerous vessels are at risk of dilation with a
high concentration of therapeutic agent present diffusely in the
extravascular space of the conjunctiva. Direct intracameral
implantation also obviates the need for preservatives, which when
used in topical drops, can irritate the ocular surface.
The implants described herein are made of polymeric materials to
provide maximal approximation of the implant to the iridocorneal
angle. In addition, the size of the implant, which ranges from a
diameter, width or cross-section of about 0.1 mm to about 1 mm, and
lengths from about 0.1 mm to about 6 mm, enables the implant to be
inserted into the anterior chamber using an applicator with a small
gauge needle ranging from about 22G to about 30G.
The polymer materials used to form the implants described herein
can be any combination of polylactic acid, glycolic acid, and/or
polyethylene glycol that provides sustained-release of the
therapeutic agent into the outflow system of the eye over time.
Other polymer-based sustained release therapeutic agent delivery
systems for hypotensive lipids can also be used intracamerally to
reduce IOP.
The intracameral implants described herein can release therapeutic
agent loads over various time periods. The implants, when inserted
intracamerally or into the anterior vitreous, provide therapeutic
levels of at least one therapeutic agent for extended periods of
time. Extended periods of time can be about 1 week, about 6 weeks,
about 6 months, about 1 year or longer.
Suitable polymeric materials or compositions for use in the
implants include those materials which are compatible, that is
biocompatible, with the eye so as to cause no substantial
interference with the functioning or physiology of the eye. Such
materials preferably are at least partially, and more preferably,
substantially biodegradable or bioerodible.
In one embodiment, examples of useful polymeric materials include,
without limitation, such materials derived from and/or including
organic esters and organic ethers, which when degraded result in
physiologically acceptable degradation products, including the
monomers. Also, polymeric materials derived from and/or including,
anhydrides, amides, orthoesters and the like, by themselves or in
combination with other monomers, may also find use. The polymeric
materials may be addition or condensation polymers, advantageously
condensation polymers. The polymeric materials may be cross-linked
or non-cross-linked, for example not more than lightly
cross-linked, such as less than about 5%, or less than about 1% of
the polymeric material being cross-linked. For the most part,
besides carbon and hydrogen, the polymers will include at least one
of oxygen and nitrogen, advantageously oxygen. The oxygen may be
present as oxy, e.g. hydroxy or ether, carbonyl, e.g.
non-oxo-carbonyl, such as carboxylic acid ester, and the like. The
nitrogen may be present as amide, cyano and amino.
In one embodiment, polymers of hydroxyaliphatic carboxylic acids,
either homopolymers or copolymers, and polysaccharides are useful
in the implants. Polyesters can include polymers of D-lactic acid,
L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof. Generally, by employing
the L-lactate or D-lactate, a slowly eroding polymer or polymeric
material is achieved, while erosion is substantially enhanced with
the lactate racemate. Useful polysaccharides and polyethers can
include, without limitation, polyethylene glycol (PEG), calcium
alginate, and functionalized celluloses, particularly
carboxymethylcellulose esters characterized by being water
insoluble and having a molecular weight of about 5 kD to about 500
kD, for example.
Other polymers of interest include, without limitation, polyvinyl
alcohol, polyesters, and combinations thereof which are
biocompatible and may be biodegradable and/or bioerodible. Some
preferred characteristics of the polymers or polymeric materials
for use in the present implants may include biocompatibility,
compatibility with the selected therapeutic agent, ease of use of
the polymer in making the therapeutic agent delivery systems
described herein, a desired half-life in the physiological
environment, and water insolubility.
In one embodiment, an intracameral implant according to the present
description has a formulation of 30% therapeutic agent, 45% R2035
poly(D,L-lactide), 20% R202H poly(D,L-lactide), and 5% PEG 3350. In
another embodiment, the formulation is 20% therapeutic agent, 45%
R2035 poly(D,L-lactide), 10% R202H poly(D,L-lactide), 20% RG752S
poly(DL-lactide-co-glycolide), and 5% PEG 3350. The range of
concentrations of the constituents that can be used are about 5% to
about 40% therapeutic agent, about 10% to about 60% R203S, about 5%
to about 20% R202H, about 5% to about 40% RG752S, and 0 to about
15% PEG 3350. Specific polymers may be omitted, and other types
added, to adjust the therapeutic agent release rates. The polymers
used are commercially available.
The polymers used to form the implant have independent properties
associated with them that when combined provide the properties
needed for sustained release of at least one therapeutic agent once
implanted. For example, R2035 poly(D,L-lactide) has an inherent
viscosity, or mean viscosity, of about 0.25 to about 0.35 dl/g
whereas R202H poly(D,L-lactide) has a lower inherent viscosity of
about 0.16 to about 0.24 dl/g. As such, the polymer compositions
described herein can have a mixture of higher and lower molecular
weight poly(D,L-lactide). Likewise, RG752S
poly(DL-lactide-co-glycolide) has a molar ratio of
D,L-lactide:glycolide of about 73:27 to about 77:23 and an inherent
viscosity of about 0.16 to about 0.24 dl/g. The polyethylene glycol
used herein can have a molecular weight for example of about 3,000
to about 3,500 g/mol, preferably about 3,350 g/mol. Polymers having
different inherent viscosities and/or molecular weights can be
combined to arrive at a polymeric composition appropriate for
sustained release of a particular therapeutic agent or agents.
The biodegradable polymeric materials which are included to form
the implant's polymeric matrix are preferably subject to enzymatic
or hydrolytic instability. Water soluble polymers may be
cross-linked with hydrolytic or biodegradable unstable cross-links
to provide useful water insoluble polymers. The degree of stability
can be varied widely, depending upon the choice of monomer, whether
a homopolymer or copolymer is employed, employing mixtures of
polymers, and whether the polymer includes terminal acid
groups.
Equally important to controlling the biodegradation of the polymer
and hence the extended release profile of the implant is the
relative average molecular weight of the polymeric composition
employed in the implants. Different molecular weights of the same
or different polymeric compositions may be included to modulate the
release profile of the at least one therapeutic agent.
The implants described herein can be monolithic, i.e. having the at
least one therapeutic agent homogenously distributed throughout the
polymeric matrix, or encapsulated, where a reservoir of therapeutic
agent is encapsulated by the polymeric matrix. In addition, the
therapeutic agent may be distributed in a non-homogenous pattern in
the matrix. For example, the implants may include a portion that
has a greater concentration of the therapeutic agent relative to a
second portion of the implant which may have less.
The total weight of an implant is dependent on the volume of the
anterior chamber and the activity or solubility of the therapeutic
agent. Often, the dose of therapeutic agent is generally about 0.1
mg to about 200 mg of implant per dose. For example, an implant may
weigh about 1 mg, about 3 mg, about 5 mg, about 8 mg, about 10 mg,
about 100 mg about 150 mg, about 175 mg, or about 200 mg, including
the incorporated therapeutic agent.
A load of therapeutic agent associated with an implant will have a
sustained release property or profile associated with it. For
example, over the first 30 days after implantation, the implants
described herein can release about 1 .mu.g/day to about 20
.mu.g/day. Over the lifetime of an implant, about 100 ng/day to
about 900 ng/day can be released. In other embodiments, about 300
ng/day, about 675 ng/day or about 700 ng/day of therapeutic agent
is released.
The proportions of the therapeutic agent, polymer and any other
modifiers may be empirically determined by formulating several
implant batches with varying average proportions. Release rates can
be estimate, for example, using the infinite sink method, a weighed
sample of the implants is added to a measured volume of a solution
containing 0.9% NaCl in water, where the solution volume will be
such that the therapeutic agent concentration after release is less
than 5% of saturation. The mixture is maintained at 37.degree. C.
and stirred slowly. The appearance of the dissolved therapeutic
agent as a function of time may be followed by various methods
known in the art, such as spectrophotometrically, HPLC, mass
spectroscopy, and the like until the absorbance becomes constant or
until greater than 90% of the therapeutic agent has been
released.
The therapeutic agents that can be used with the implants described
herein are prostaglandins, prostaglandin analogues, and
prostamides. Examples include prostaglandin receptor agonists
including prostaglandin E.sub.1 (alprostadil), prostaglandin
E.sub.2 (dinoprostone), latanoprost and travoprost. Latanoprost and
travoprost are prostaglandin prodrugs (i.e. I-isopropyl esters of a
prostaglandin); however, they are referred to as prostaglandins
because they act on the prostaglandin F receptor, after being
hydrolyzed to the 1-carboxylic acid. A prostamide (also called a
prostaglandin-ethanolamide) is a prostaglandin analogue, which is
pharmacologically unique from a prostaglandin (i.e. because
prostamides act on a different cell receptor [the prostamide
receptor] than do prostaglandins), and is a neutral lipid formed a
as product of cyclo-oxygenase-2 ("COX-2") enzyme oxygenation of an
endocannabinoid (such as anandamide). Additionally, prostamides do
not hydrolyze in situ to the 1-carboxylic acid. Examples of
prostamides are bimatoprost (the synthetically made ethyl amide of
17-phenyl prostaglandin F.sub.2.alpha.) and prostamide
F.sub.2.alpha.. Other prostaglandin analogues that can be used as
therapeutic agents include, but are not limited to, unoprostone,
and EP.sub.2/EP.sub.4 receptor agonists.
Prostaglandins as used herein also include one or more types of
prostaglandin derivatives, prostaglandin analogues including
prostamides and prostamide derivatives, prodrugs, salts thereof,
and mixtures thereof. In certain implants, the prostaglandin
comprises a compound having the structure
##STR00001## wherein the dashed bonds represent a single or double
bond which can be in the cis or trans configuration; A is an
alkylene or alkenylene radical having from two to six carbon atoms,
which radical may be interrupted by one or more oxide radicals and
substituted with one or more hydroxy, oxo, alkyloxy or akylcarboxy
groups wherein the alkyl radical comprises from one to six carbon
atoms; B is a cycloalkyl radical having from three to seven carbon
atoms, or an aryl radical, selected from hydrocarbyl aryl and
heteroaryl radicals having from four to ten carbon atoms wherein
the heteroatom is selected from nitrogen, oxygen and sulfur atoms;
X is --OR.sup.4 or --N(R.sup.4).sub.2 wherein R.sup.4 is selected
from hydrogen, a lower alkyl radical having from one to six carbon
atoms,
##STR00002## wherein R.sup.5 is a lower alkyl radical having from
one to six carbon atoms; Z is .dbd.O or represents two hydrogen
radicals; one of R.sup.1 and R.sup.2 is .dbd.O, --OH or a
--O(CO)R.sup.6 group, and the other one is --OH or --O(CO)R.sup.6,
or R.sup.1 is .dbd.O and R.sup.2 is hydrogen, wherein R.sup.6 is a
saturated or unsaturated acyclic hydrocarbon group having from 1 to
about 20 carbon atoms, or --(CH2).sub.mR.sup.7 wherein m is 0 or an
integer of from 1 to 10, and R.sup.7 is cycloalkyl radical, having
from three to seven carbon atoms, or a hydrocarbyl aryl or
heteroaryl radical, as defined above, or a
pharmaceutically-acceptable salt thereof.
Pharmaceutically acceptable acid addition salts of the compounds
described are those formed from acids which form non-toxic addition
salts containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate,
phosphate or acid phosphate, acetate, maleate, fumarate, oxalate,
lactate, tartrate, citrate, gluconate, saccharate and p-toluene
sulphonate salts.
In one example embodiment, the implants include a prostaglandin
having the structure
##STR00003## wherein y is 0 or 1, x is 0 or 1 and x and y are not
both 1, Y is selected the group consisting of alkyl, halo, nitro,
amino, thiol, hydroxy, alkyloxy, alkylcarboxy and halo substituted
alkyl, wherein said alkyl radical comprises from one to six carbon
atoms, n is 0 or an integer of from 1 to 3 and R.sup.3 is .dbd.O,
--OH or O(CO)R.sup.6.
In additional example embodiments, the prostaglandin has the
formula
##STR00004## wherein hatched lines indicate the alpha configuration
and solid triangles indicate the beta configuration.
In some implants described herein, the prostaglandin has the
formula
##STR00005## wherein Y.sup.1 is Cl or trifluoromethyl.
Other prostaglandins can have the following formula
##STR00006## and 9-, 11- and/or 15 esters thereof.
In one example embodiment, the prostaglandin component comprises a
compound having the formula
##STR00007##
This compound is also known as bimatoprost and is publicly
available in a topical ophthalmic solution under the tradename,
LUMIGAN.RTM. (Allergan, Inc., Irvine, Calif.).
In another example embodiment of an intraocular implant, the
prostaglandin comprises a compound having the structure
##STR00008##
This prostaglandin is known as latanoprost and is publicly
available in a topical ophthalmic solution under the tradename,
XALATAN.RTM.. Thus, the implants may comprise at least one
therapeutic bioactive agent which comprises, consists essentially
of, or consists of latanoprost, a salt thereof, isomer, prodrug or
mixtures thereof.
The prostaglandin component may be in a particulate or powder form
and it may be entrapped by the biodegradable polymer matrix.
Usually, prostaglandin particles will have an effective average
size less than about 3000 nanometers. In certain implants, the
particles may have an effective average particle size about an
order of magnitude smaller than 3000 nanometers. For example, the
particles may have an effective average particle size of less than
about 500 nanometers. In additional implants, the particles may
have an effective average particle size of less than about 400
nanometers, and in still further embodiments, a size less than
about 200 nanometers.
Other therapeutic agents useful with the intracameral implants
described herein, include, but are not limited to beta-adrenergic
receptor antagonists (such as timolol, betaxolol, levobetaxolol,
carteolol, levobunolol, and propranolol, which decrease aqueous
humor production by the ciliary body); alpha adrenergic receptor
agonists such as brimonidine and apraclonidine (iopidine) (which
act by a dual mechanism, decreasing aqueous production and
increasing uveoscleral oufflow); less-selective sympathomimetics
such as epinephrine and dipivefrin (act to increase oufflow of
aqueous humor through trabecular meshwork and possibly through
uveoscleral oufflow pathway, probably by a beta 2-agonist action);
carbonic anhydrase inhibitors such as dorzolamide, brinzolamide,
acetazolamide (lower secretion of aqueous humor by inhibiting
carbonic anhydrase in the ciliary body); rho-kinase inhibitors
(lower IOP by disrupting the actin cytoskeleton of the trabecular
meshwork; vaptans (vasopressin-receptor antagonists); anecortave
acetate and analogues; ethacrynic acid; cannabinoids; cholinergic
agonists including direct acting cholinergic agonists (miotic
agents, parasympathomimetics) such as carbachol, pilocarpine
hydrochloride; pilocarbine nitrate, and pilocarpine (acts by
contraction of the ciliary muscle, tightening the trabecular
meshwork and allowing increased outflow of the aqueous humor);
chlolinesterase inhibitors such as demecarium, echothiophate and
physostigmine; glutamate antagonists; calcium channel blockers
including memantine, amantadine, rimantadine, nitroglycerin,
dextrophan, detromethorphan, dihydropyridines, verapamil, emopamil,
benzothiazepines, bepridil, diphenylbutylpiperidines,
diphenylpiperazines, fluspirilene, eliprodil, ifenprodil,
tibalosine, flunarizine, nicardipine, nifedimpine, nimodipine,
barnidipine, verapamil, lidoflazine, prenylamine lactate and
amiloride; prostamides such as bimatoprost, or pharmaceutically
acceptable salts or prodrugs thereof; and prostaglandins including
travoprost, chloprostenol, fluprostenol,
13,14-dihydro-chloprostenol, isopropyl unoprostone, and
latanoprost; AR-I 02 (a prostaglandin FP agonist available from
Aerie Pharmaceuticals, Inc.); AL-3789 (anecortave acetate, an
angiostatic steroid available from Alcon); AL-6221 (travaprost
rravatan] a prostaglandin FP agonist; PF-03187207 (a nitric oxide
donating prostaglandin available from by Pfizer) PF-04217329 (also
available from Pfizer); INS1 15644 (a lantrunculin B compound
available from Inspire Pharmaceuticals), and; INS1 17548
(Rho-kinase inhibitor also available from inspire
Pharmaceuticals).
Combinations of ocular anti-hypertensives, such as a beta blocker
and a prostaglandin/prostamide analogue, can also be used in the
delivery systems described herein. These include
bimatoprostltimolol, travoprostltimolol, latanoprostltimolol,
brimonidine/timolol, and dorzolamide/timolol. In combination with
an IOP lowering therapeutic agent, an agent that confers
neuroprotection can also be placed in the delivery system and
includes memantine and serotonergics [e.g., 5-HT.sub.2 agonists,
such as but no limited to,
S-(+)-I-(2-aminopropyl)-indazole-6-01)].
Other therapeutic agents outside of the class of ocular hypotensive
agents can be used with the intracameral implants to treat a
variety of ocular conditions. For example, anti-VEGF and other
anti-angiogenesis compounds can be used to treat neovascular
glaucoma. Another example is the use of corticosteroids or
calcineurin inhibitors that can be used to treat diseases such as
uveitis and corneal transplant rejection. These implants can also
be placed in the subconjunctival space and in the vitreous.
Additionally, described herein are novel methods for making
implants. The therapeutic agent of the present implants is
preferably from about 1% to about 90% by weight of the implant.
More preferably, the therapeutic agent is from about 5% to about
30% by weight of the implant. In a preferred embodiment, the
therapeutic agent is an anti-hypertensive agent and comprises about
15% by weight of the implant (e.g., 5%-30 weight %). In another
embodiment, the anti-hypertensive agent comprises about 20% or
about 30% by weight of the implant.
In addition to the therapeutic agent, the implants described herein
can include or may be provided in compositions that include
effective amounts of buffering agents, preservatives and the like.
Suitable water soluble buffering agents include, without
limitation, alkali and alkaline earth carbonates, phosphates,
bicarbonates, citrates, borates, acetates, succinates and the like,
such as sodium phosphate, citrate, borate, acetate, bicarbonate,
carbonate and the like. These agents can be present in amounts
sufficient to maintain a pH of the system of between about 2 to
about 9 and more preferably about 4 to about 8. As such the
buffering agent may be as much as about 5% by weight of the total
implant. Suitable water soluble preservatives include sodium
bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric
acetate, phenylmercuric borate, phenylmercuric nitrate, parabens,
methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol and
the like and mixtures thereof. These agents may be present in
amounts of from about 0.001% to about 5% by weight and preferably
about 0.01% to about 2% by weight of the implant.
In one embodiment, a preservative such as benzylalkonium chloride
is provided in the implant. In another embodiment, the implant can
include both benzylalkonium chloride and bimatoprost. In yet
another embodiment, the bimatoprost is replaced with
latanoprost.
Various techniques may be employed to produce the implants
described herein. Useful techniques include, but are not
necessarily limited to, self-emulsification methods, super critical
fluid methods, solvent evaporation methods, phase separation
methods, spray drying methods, grinding methods, interfacial
methods, molding methods, injection molding methods, combinations
thereof and the like.
In one embodiment, the methods for making the implants involve
dissolving the appropriate polymers and therapeutic agents in a
solvent. Solvent selection will depend on the polymers and
therapeutic agents chosen. For the implants described herein,
including a therapeutic agent such as latanoprost, dichloromethane
(DCM) is an appropriate solvent. Once the polymers and therapeutic
agent(s) have been dissolved, the resulting mixture is cast into a
die of an appropriate shape.
Then, once cast, the solvent used to dissolve the polymers and
therapeutic agent(s) is evaporated at a temperature between about
20.degree. C. and about 30.degree. C., preferably about 25.degree.
C. The polymer can be dried at room temperature or even in a
vacuum. For example, the cast polymers including therapeutic agents
can be dried by evaporation in a vacuum.
The dissolving and casting steps form the implants because
dissolving the polymers and therapeutic agents allows the system to
naturally partition and form into its most natural configuration
based on properties such as polymer viscosity and hence molecular
weight, polymer hydrophobicity/hydophilicty, therapeutic agent
molecular weight, therapeutic agent hydrophobicity/hydophilicty and
the like.
Once the cast polymers are dried, they can be processed into an
implant using any method known in the art to do so. In an example
embodiment, the dried casted polymer can be cut into small pieces
and extruded into rounded or squared rod shaped structures at a
temperature between about 50.degree. C. and about 120.degree. C.,
preferably about 90.degree. C. In other example embodiments, the
films can simply be cast without extrusion.
Other methods involve extrusion of dry polymer powders and dry or
liquid therapeutic agents. The implants are extruded and formed
into a random orientation depending on the dry powder mix itself
and not based on physical properties of the components.
Prostaglandins such as latanoprost are very difficult to
incorporate into hot-melt extruded implants because they generally
exude the prostaglandin when heated. Therefore, the extrusion
temperature is kept as low as possible to avoid loss and
degradation of the prostaglandin. This can be accomplished by using
a select combination of appropriate molecular weight polymers and a
plasticizer like (polyethyleneglycol) PEG that are compatible with
the prostaglandin. The prostaglandin and PEG plasticize the
polymers to a degree that allows the mixture to be extruded at a
temperature where the prostaglandin is not degraded or lost.
The therapeutic agent containing implants disclosed herein can be
used to treat other ocular conditions in addition to glaucoma
and/or increased IOP, such as the following: maculopathies/retinal
degeneration: macular degeneration, including age related macular
degeneration (ARMD), such as non-exudative age related macular
degeneration and exudative age related macular degeneration,
choroidal neovascularization, retinopathy, including diabetic
retinopathy, acute and chronic macular neuroretinopathy, central
serous chorioretinopathy, and macular edema, including cystoid
macular edema, and diabetic macular edema.
Uveitis/retinitis/choroiditis: acute multifocal placoid pigment
epitheliopathy, Behcet's disease, birdshot retinochoroidopathy,
infectious (syphilis, lyme, tuberculosis, toxoplasmosis), uveitis,
including intermediate uveitis (pars planitis) and anterior
uveitis, multifocal choroiditis, multiple evanescent white dot
syndrome (MEWDS), ocular sarcoidosis, posterior scleritis,
serpignous choroiditis, subretinal fibrosis, uveitis syndrome, and
Vogt-Koyanagi-Harada syndrome. Vascular diseases/exudative
diseases: retinal arterial occlusive disease, central retinal vein
occlusion, disseminated intravascular coagulopathy, branch retinal
vein occlusion, hypertensive fundus changes, ocular ischemic
syndrome, retinal arterial microaneurysms, Coat's disease,
parafoveal telangiectasis, hemi-retinal vein occlusion,
papillophlebitis, central retinal artery occlusion, branch retinal
artery occlusion, carotid artery disease (CAD), frosted branch
angitis, sickle cell retinopathy and other hemoglobinopathies,
angioid streaks, familial exudative vitreoretinopathy, Eales
disease. Traumatic/surgical: sympathetic ophthalmia, uveitic
retinal disease, retinal detachment, trauma, laser, PDT,
photocoagulation, hypoperfusion during surgery, radiation
retinopathy, bone marrow transplant retinopathy. Proliferative
disorders: proliferative vitreal retinopathy and epiretinal
membranes, proliferative diabetic retinopathy. Infectious
disorders: ocular histoplasmosis, ocular toxocariasis, presumed
ocular histoplasmosis syndrome (PONS), endophthalmitis,
toxoplasmosis, retinal diseases associated with HIV infection,
choroidal disease associated with HIV infection, uveitic disease
associated with HIV Infection, viral retinitis, acute retinal
necrosis, progressive outer retinal necrosis, fungal retinal
diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral
subacute neuroretinitis, and myiasis. Genetic disorders: retinitis
pigmentosa, systemic disorders with associated retinal dystrophies,
congenital stationary night blindness, cone dystrophies,
Stargardt's disease and fundus flavimaculatus, Bests disease,
pattern dystrophy of the retinal pigmented epithelium, X-linked
retinoschisis, Sorsby's fundus dystrophy, benign concentric
maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma
elasticum. Retinal tears/holes: retinal detachment, macular hole,
giant retinal tear. Tumors: retinal disease associated with tumors,
congenital hypertrophy of the RPE, posterior uveal melanoma,
choroidal hemangioma, choroidal osteoma, choroidal metastasis,
combined hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, intraocular lymphoid tumors. Miscellaneous:
punctate inner choroidopathy, acute posterior multifocal placoid
pigment epitheliopathy, myopic retinal degeneration, acute retinal
pigment epithelitis and the like.
In one example embodiment, an implant comprising both PLA, PEG and
PLGA and including an anti-hypertensive agent is used because
implants of such a composition result in significantly less
inflammatory (e.g. less corneal hyperemia) upon intracameral or
anterior vitreal administration. Another embodiment can comprise a
therapeutic agent delivery system with a plurality of
anti-hypertensive agents contained in different segments of the
same implant. For example, one segment of an implant can contain a
muscarinic anti-hypertensive agent, a second segment of the implant
can contain a anti-hypertensive prostaglandin and third segment of
the implant can contain an anti-hypertensive beta blocker. Such an
implant can be injected to enhance aqueous outflow through the
trabecular meshwork, to enhance uveoscleral flow and to reduce
aqueous humor production. Multiple hypotensive agents with
different mechanisms of action can be more effective at lowering
IOP than monotherapy, that is use of a single type of an
anti-hypertensive agent. A multiple segmented implant has the
advantage of permitting lower doses of each separate therapeutic
agent used than the dose necessary with monotherapy, thereby
reducing the side effects of each therpaeutic agent used.
In one embodiment, when using a multiple segmented implant, each
segment is preferably has a length no greater than about 2 mm.
Preferably, the total umber of segments administered through a 22G
to 25G diameter needle bore is about four. With a 27G diameter
needle total segments length within the needle bore or lumen can be
up to about 12 mm.
The fluid uptake action of the TM can be exploited to keep implants
that have an appropriate geometry from floating around the anterior
chamber causing visual obscuration. Gravity brings these implants
down to about the 6 o'clock position, for example from about 20
degrees plus or minus, and the implants are stable (immobile) in
this position. Implants that can be intraocularly administered by a
22G to 30G diameter needle with lengths totaling no more than about
6 to 8 mm are most preferred to take advantage of the TM fluid
uptake mechanism with resulting intraocular implant immobility and
no visual obscuration. Thus, despite being firmly in the 6 o'clock
position in the anterior chamber due to TM fluid uptake effect, the
implants can have release rates that exceed the TM clearance rate
and this allows therapeutic agent(s) released by the implants to
rapidly fill the anterior chamber and distribute well into the
target tissues along a 360 degrees distribution pattern.
Examination of implants in the angle of the anterior chamber with
gonioscopy have shown that the there is no encapsulation of nor
inflammatory tissue in the vicinity of the implants.
Delivery of therapeutic agents to the front of the eye (anterior
chamber) can both lower intraocular pressure (IOP) and evade
aggressive clearance of the transscleral barriers. Intracameral
injections (i.e. direct injection into the anterior chamber) of
implants as described herein and anterior vitreous injections of
the same through the pars plana effectively avoid the transscleral
barriers and improve the efficacy of the ocular anti-hypertensive
compounds. Importantly, the present implants required development
of new sustained released therapeutic agent delivery systems with
particular physical features and required therapeutic efficacy
because of the unique anatomy and physiology of the anterior
chamber.
In one example embodiment, bimatoprost can be used in the implants
described herein. Bimatoprost may improve aqueous outflow through
the trabecular meshwork (TM) mediated through a prostamide
receptor. In the human eye, the main outflow route is the
trabecular or conventional outflow pathway. This tissue contains
three differentiated layers. From the inner to the outermost part,
the layer of tissue closest to the anterior chamber is the uveal
meshwork, formed by prolongations of connective tissue arising from
the iris and ciliary body stromas and covered by endothelial cells.
This layer does not offer much resistance to aqueous humor outflow
because intercellular spaces are large. The next layer, known as
the corneoscleral meshwork, is characterized by the presence of
lamellae covered by endothelium-like cells on a basal membrane. The
lamellae are formed by glycoproteins, collagen, hyaluronic acid,
and elastic fibers. The higher organization of the corneoscleral
meshwork, in relation to the uveal meshwork, as well as their
narrower intercellular spaces, are responsible for the increase in
flow resistance. The third layer, which is in direct contact with
the inner wall of endothelial cells from Schlemm's canal, is the
juxtacanalicular meshwork. It is formed by cells embedded in a
dense extracellular matrix, and the majority of the tissue
resistance to aqueous flow is postulated to be in this layer, due
to its narrow intercellular spaces. The layer of endothelial cells
from Schlemm's canal has expandable pores that transfer the aqueous
into the canal and accounts for approximately 10% of the total
resistance. It is thought that aqueous humor crosses the inner wall
endothelium of Schlemm's canal by two different mechanisms: a
paracellular route through the junctions formed between the
endothelial cells and a transcellular pathway through intracellular
expandable pores of the same cells. Once there is entry into
Schlemm's canal (FIG. 2), the aqueous drains directly into the
collector ducts and aqueous veins that anastomose with the
episcleral and conjunctival plexi of vessels. Aqueous humor outflow
via the trabecular pathway is IOP dependent, usually measured as
outflow facility, and expressed in microliters per minute per
millimeter of mercury.
The episcleral venous pressure controls outflow through the
collector channels and is one factor that contributes to the
intraocular pressure. Increases in the episcleral venous pressure
such as seen with carotid-cavernous sinus fistulas, orbital
varices, and Sturge-Weber Syndrome, can lead to difficult to manage
glaucoma. Reducing episcleral venous pressure in disease states,
such as treating carotid-cavernous sinus fistulas, can normalize
the episcleral venous pressure and reduce the intraocular pressure.
Targeting the outflow channels and vessels to reduce the episcleral
venous pressure with pharmacotherapy may reduce the IOP.
Example 1
A series of three experiments were performed comparing the
fluctuations of IOP over time in groups of animals treated with
either bimatoprost eye drops or an intracameral sustained release
bimatoprost implant as described herein. IOPs were recorded over
time and the mean of the IOPs for each animal was calculated after
dosing. The standard deviation (SD) of the mean was used to compare
the variability of IOP control for each animal, and the average of
all the SD means was calculated. A lower number for example, would
correspond to less IOP fluctuation. This final SD value was
calculated for all animals in the topical dosed group and also
calculated for all animals receiving an intracameral implant, and
the values were compared to determine if the intracameral implants
were more effective at reducing IOP fluctuation.
Experiment 1:
Six normal beagle dogs had one drop bimatoprost 0.03% ophthalmic
solution (LUMIGAN.RTM.) instilled in the left eye daily. Recordings
of IOP were made with a pneumatonometer at about 10 am. Table 1
displays IOP recordings in mmHG at weekly intervals for 1 month in
6 dogs taking daily bimatoprost eye drops. The average of the mean
of the SD for each animal is 1.38 mm Hg.
TABLE-US-00001 TABLE 1 Bimatoprost 0.03% Ophthalmic Drops: IOP
Results Dog A Dog B Dog C Dog D Dog E Dog F Baseline 15.7 20.2 16.5
20.7 12.7 20.7 IOP (mmHG) Day 8 8.3 8.0 9.7 10.0 10.0 7.5 Day 15
7.2 6.2 8.8 9.0 6.8 10.3 Day 22 8.5 7.8 12.8 9.2 7.5 14.5 Day 29
9.0 7.7 11.7 9.3 9.5 11.3 Mean 8.3 7.4 10.8 9.4 8.5 10.9 SD 0.76
0.83 1.83 0.43 1.54 2.89
Experiment 2:
A bimatoprost implant with a formulation containing 30% therapeutic
agent, 45% R203S, 20% R202H and 5% PEG 3350 was manufactured with a
total implant weight of 900 ug (drug load 270 ug). The in vitro
release rates of this implant are graphically illustrated in FIG.
4. This implant released about 70% over first 30 days. An implant
with a 270 ug drug load would release 189 ug over first 30 days or
6.3 ug per day. The remainder of the implant (81 ug) is released
over the next four months (e.g. 675 ng per day).
Normal beagle dogs were given general anesthesia and a 3 mm wide
keratome blade was used to enter the anterior chamber of the right
eyes. A bimatoprost implant was placed in the anterior chamber and
it settled out in the inferior angle within 24 hours. The IOP
results are shown in Table 2. The average of the mean of the SD for
each animal is 0.57 mm Hg with Dog #4 having a first month mean SD
of 0.
TABLE-US-00002 TABLE 2 Intracameral Bimatoprost Implant: IOP
Results Dog #1 Dog #2 Dog #3 Dog #4 120 ug 120 ug 120 ug 270 ug
Baseline IOP 17.0 16.5 22.5 25.0 (mmHG) Day 7 11.5 9.0 14.0 9.0 Day
14 10.5 9.0 14.5 n/a Day 21 11.5 11.0 13.5 n/a Day 28 11.0 11.0
13.0 9.0 Mean 11.1 10.0 13.8 9.0 SD 0.48 1.15 0.65 0
Experiment 3:
An additional bimatoprost implant formulation with 20% therapeutic
agent, 45% R203S, 10% R202H, 20% RG752S and 5% PEG 3350 formulation
was manufactured with a total implant weight of about 300 ug (drug
load of about 60 ug). Implant weights are shown in Table 3, each
animal received two implants. The in vitro release rates of this
implant are shown in FIG. 5. Table 3 shows implant weights and
therapeutic agent loads used in the dogs for Experiment 3. Each
animal received 2 intracameral implants to 1 eye. The implants
release about 15% of the drug load over the first month. An implant
with a 60 ug drug load would release 9 ug over the first 30 days or
300 ng per day, thereafter. In other words, the implant releases
about 50 ug over 60 days or about 700 ng/day.
TABLE-US-00003 TABLE 3 Implant weights Implant Weight Total
Therapeutic Agent Dog ID (mg) Dose (20% load, ug) Dog #1 0.302
126.6 0.331 Dog #2 0.298 125.4 0.329 Dog #3 0.0306 126.6 0.327
Implants were loaded in customized applicators with a 25G UTW
needles. Under general anesthesia, normal beagle dogs had the
implant inserted in the right anterior chamber through clear cornea
and the wound was self-sealing. Each animal (n=3) received two
implants in the right eye. The implant demonstrated no inflammation
clinically and a representative photograph of an implant in the
anterior chamber is seen in FIG. 6. The IOP results and the SD of
the mean over the first month are shown in Table 2. The average of
the mean of the SD's in Table 2 of the four dogs (total) from
experiments 2 and 3 treated with bimatoprost implants was 0.57
mmHg.
The variability in the IOP of the dogs in Experiment 1 dosed with
bimatoprost eye drops as measured by the final SD value was 1.38
mmHg. In contrast, the final SD value with sustained-release
bimatoprost implants was 0.57 mmHg. There was approximately a
three-fold reduction in the final SD value demonstrating that
sustained-release bimatoprost implant described herein is superior
to bolus dosing with topical bimatoprost to reduce IOP fluctuations
over time.
Unless otherwise indicated, all numbers expressing quantities of
ingredients, properties such as molecular weight, reaction
conditions, and so forth used in the specification and claims are
to be understood as being modified in all instances by the term
"about." Accordingly, unless indicated to the contrary, the
numerical parameters set forth in the specification and attached
claims are approximations that may vary depending upon the desired
properties sought to be obtained by the present invention. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, each numerical
parameter should at least be construed in light of the number of
reported significant digits and by applying ordinary rounding
techniques. Notwithstanding that the numerical ranges and
parameters setting forth the broad scope of the invention are
approximations, the numerical values set forth in the specific
examples are reported as precisely as possible. Any numerical
value, however, inherently contains certain errors necessarily
resulting from the standard deviation found in their respective
testing measurements.
The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
Groupings of alternative elements or embodiments of the invention
disclosed herein are not to be construed as limitations. Each group
member may be referred to and claimed individually or in any
combination with other members of the group or other elements found
herein. It is anticipated that one or more members of a group may
be included in, or deleted from, a group for reasons of convenience
and/or patentability. When any such inclusion or deletion occurs,
the specification is deemed to contain the group as modified thus
fulfilling the written description of all Markush groups used in
the appended claims.
Certain embodiments of this invention are described herein,
including the best mode known to the inventors for carrying out the
invention. Of course, variations on these described embodiments
will become apparent to those of ordinary skill in the art upon
reading the foregoing description. The inventor expects skilled
artisans to employ such variations as appropriate, and the
inventors intend for the invention to be practiced otherwise than
specifically described herein. Accordingly, this invention includes
all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law.
Moreover, any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
Furthermore, numerous references have been made to patents and
printed publications throughout this specification. Each of the
above-cited references and printed publications are individually
incorporated herein by reference in their entirety.
In closing, it is to be understood that the embodiments of the
invention disclosed herein are illustrative of the principles of
the present invention. Other modifications that may be employed are
within the scope of the invention. Thus, by way of example, but not
of limitation, alternative configurations of the present invention
may be utilized in accordance with the teachings herein.
Accordingly, the present invention is not limited to that precisely
as shown and described.
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